Phenylacetic acids

ABSTRACT

Novel Alpha -alkyl- Alpha -mercapto-p-cycloalkylphenylacetic acids and their derivatives have been prepared. Compounds of this invention possess useful anti-inflammatory, analgesic and antipyretic properties.

United States Patent [191 Diamond et al.

[4 1 July 8,1975

[ PHENYLACETIC ACIDS [75] Inventors: Julius Diamond, Lafayette Hill;

Norman Julian Santora, Roslyn, both of Pa.

[73] Assignee: William H. Roi-er, Inc., Fort Washington, Pa.

22 Filed: Jan. 7, 1974 21 Appl. No.: 431,502

Related US. Application Data [63] Continuation of Ser. No. 152,368, Jan.11, 1971, abandoned, which is a continuation-in-part of Ser. No. 34,870,May 5, 1970.

[52] US. Cl. 260/516; 260/141; 260/239 BC; 260/247.2 R; 260/247.2 A;260/247.2 B;

260/247.5 R; 260/247.7 R; 260/247.7 A;

260/247.7 H; 260/247.7 K; 260/268 R;

260/268 C; 260/268 MK; 260/268 CN;

Primary Examiner-John F. Terapane Attorney, Agent, or Firm-Erich M. H.Radde [57] ABSTRACT Novel oz-alkyl-oz-mercapto-p-cycloalkylphenylaceticacids and their derivatives have been prepared. Compounds of thisinvention possess useful antiinfiammatory, analgesic and antipyreticproperties.

A '6 Claims, No Drawings PHENYLACETIC Acins CROSS REFERENCES TO RELATEDAPPLICATIONS This is a continuation of application Ser. No. 152,368filed Jan. 1 1, 1971, now abandoned, which is a continuation in part ofSer. No. 34,870, filed May 5, 1970.

SUMMARY OF THE INVENTION This invention describes certaina-mercapto-pcycloalkylphenylacetic acids and their derivatives and theiruse in therapeutic compositions. In addition. this invention relates tothe preparation of these a-mercapto-p-cycloalkylphenylacetic acids. Whenthe compounds of this invention are administered to mammals, they affordsignificant treatment of inflammation and associated pain and fever.

They further provide analgesic and antipyretic methods for the reliefand treatment of pain and fever associated with inflammation.

BACKGROUND OF THE INVENTION There has been continued efforts in researchto develop drugs which would significantly inhibit the development ofinflammation and relieve the pain and fever associated with it. Much ofthese efforts have been car ried on in the field of steroids. While manyof these compounds have been effective, they have had the drawback ofcausing many side effects.

We have unexpectedly found that a-mercapto-pcycloalkylphenylacetic acidcompounds and their derivatives have valuable pharmacologic properties.

We have found that a-mercapto-p-cycloalkylphenylacetic acid compoundsand their derivatives possess useful anti-inflammatory, analgesic andantipyretic properties.

We have also found a series of anti-inflammatory compounds which arenon-steroidal.

We have further found that these oz-mercaptopcycloalkylphenylacetic acidcompounds and their derivatives are novel.

We have also found that the compounds of this invention are useful ineffectively providing a method for the inhibition of inflammation andthe treatment of associated pain and fever.

We have still further found an entirely new class of anti-inflammatory,analgesic and antipyretic pharmaceutical compositions containing thea-mercapto-pcycloalkylphenylacetic acids and derivatives of thisinvention as active ingredient.

We have again found a convenient method for synthesizing thesecompounds.

DESCRIPTION AND PREFERRED EMBODIMENT This invention comprises a class ofnovel chemical compounds which contain a cycloalky] radical which isattached to a substituted phenyl-oz-mercaptoacetic acid in thepara-position. This invention further comprises derivatives of saidacetic acids and the method of preparing the same.

This invention also describes a new method of treating inflammation andassociated pain and fever as well as novel therapeutic compositions.

The compounds of this invention can be represented by the genericstructure which is described by the general formula I where: R isloweralkyl;

n is 0-2; B is hydrogen or loweralkyl; R is halo, nitro, amino,acylamino, monoand diloweralkylamino, mercapto, acylthio,loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, hydroxy,loweralkoxy', acyloxy, haloloweralkyl,

cyano, acetyl or loweralkyl; R is hydrogen, fluoro, chloro, bromo,trifluoromethyl, cyano, nitro or loweralkylsulfonyl; X is mercapto,acylthio, carboxyacylthio. aroylthio, carboxyaroylthio,loweralkoxythiocarbonylthio, loweralkoxycarbonylthio,arloweralkoxycarbonylthio, amidinothio, thiocyanato, thiosulfo,thioacylthio, diloweralkylthiocarbamylthio, carbamylthio,loweralkylcarbamylthio, diloweralkylcarbamylthio, loweralkylthio,loweralkylsulfinyl, loweralkylsulfonyl, sulfino or sulfo; and Z is OI-I,Ioweralkoxy, arloweralkoxy, 2, loweralkylamino, diloweralkylamino,cycloloweralkylamino,

N:A (where A is loweralkylidenyl or heteroloweralkylidenyl),

NHOH,

OM (where M is an alkali,'alkaline num metal or an am moniumsalt).

The compounds of this invention contain an asymmetric carbon atom in thealpha-position of the acetic acid side chain. As a result; the abovecompounds of formula I may be obtained as racemic mixtures oft he irdextro and levorotatory isomers. It is to be understood that said d andlisomers as well as thedl mixtures thereof are embraced within thescopeof thisinvention.

When B is loweralkyl, two racemic mixtures may exist in the case of 2- vor I 3- loweralkylcyclohexylphenylwmercaptoacetate, -2 or3'-loweralkylcyclopentylphenyl-d-mercaptoacetate, 2- or 3'- or4'-lower-alkylcycloheptylphenyl-amercaptoacetate or their derivatives.It is understood that both racemic mixtures are embraced within thescope of this invention.

The preferred R and R substituents are in the and earth or alumi- 5positions.

The preferred compounds of this embodiment describe the cyclohexyl classof chemical compounds which have particular usefulness asanti-inflammatory, analgesic and antipyretic agents. These compounds aredescribed in formula II la-cor a R --'-11 where:

R is loweralkyl; and I R, R, X and Z are as'described above. 7 Those,compounds whose properties are even more preferred are also described byformula ll where:

Rishalo, 1

nitro, loweralkylsulfonyl, haloloweralkyl or cyano; R is hydrogen,chloro, bromo or nitro; X is mercapto, acylthio, aroylthio,loweralkoxythiocarbonylthio,

loweralkoxycarbonylthio, amidinothio, thiocyanato, thiosulfo,carbamylthio, loweralkylcarbamylthio, diloweralkylcarbamylthio,loweralkylthio, loweralkylsulfinyl, loweralkylsulfonyl, sulfino orsulfo; and Z is OH, loweralkoxy,

arloweralkoxy,

loweralkylamino or The most preferred compounds of this inventiondescribe a class of chemical compounds which have particular usefulnessas anti-inflammatory, analgesic and antipyretic agents. These compoundsare described in formula II.

where: g

Q R; isloweralkyl;

R is halo, n loweralkylsulfonyl, I

halolower alkyl or cyano;

R is hydrogen,

chloro,

bromo or nitro;

X is mercapto,

acylthio,

aroylthio,

loweralkoxythiocarbonylthio,

loweralkoxycarbonylthio,

thiosulfo,

,carbamylthio, loweralkylcarbamylthio,

diloweralkylcarbamylthio; and

Z is Ol-l, i

' .loweralkoxy,

arlowera lkoxy, N zv loweralkylamino or A special embodiment of thisinvention which describes novel compounds that are effective ininhibiting inflammation and the treatment of pain and fever associatedwith inflammation as well as having analgesic and antipyreticeffectiveness for the relief and treatment of pain and fever notsymptomatically related to an inflammation indication are described byformula III i; i v 111 .where: v

R is loweralkyl; R is chloro, bromo,' nitro, methylsulfonyl,trifluoromethyl or cyano; .R is chloro,

bromo or acyl,

aroyl, v

loyveralkoxythiocarbonyl, loweralkoxycarbonyl, i

sulfo,

carbamyl,

loweralkylcarbamyl,

diloweralkylcarbamyl; and the salts thereof.

Included within the scope of this further special embodiment are theracemic mixtures as well as the dextro and levorotatory isomers thereof.

In the descriptive portions of this invention, the following definitionsapply:

The term loweralkyl refers to a loweralkyl hydrocarbon group containingfrom 1 to about 6 carbon atoms which may be straight chained orbranched.

The acyl radical may be any organic radical derived from an organic acidby the removal of its hydroxyl group such as formyl, acetyl, propionyl,3-carboxypropionyl, 3-carboxy-2-propenoyl, camphoryl, benzoyl, toluoylor heteroyl such as pyridinoyl, piperidinoyl, thenoyl, etc.

Loweralkoxy signifies an alkoxy group containing from 1 to about 6carbon atoms which may be straight chained or branched.

The preferred aroyl is benzoyl, loweralkylbenzoyl such as toluoyl orhalobenzoyl such as p-chlorobenzoyl, Z-carboxybenzoyl, etc.

The term loweralkylidenyl refers to a loweralky lidenyl hydrocarbongroup containing from 2 to about 6 carbon atoms.

Heterloweralkylidenyl refers to a loweralkylidenyl hydrocarbon groupcontaining from about 2 to 5 carbon atoms and having one or more heteroatoms in the chain selected from O, N or S, such as piperidinyl,morpholinyl, etc.

The preferred alkali" or alkaline earth metals are sodium, potassium,calcium and magnesium.

The term ammonium salt refers to the cation formed when ammonia or anorganic amine react with the carboxyl group to form ammonium salts ofthe structure given in the formula. The ammonium salts are formed with a(l) loweralkylamines such as methylamine, diethylamine, triethylamine;(2) hydroxyloweralkylamines such as B-hydroxyethylamine, (3)heterocyclic amines such as 2-aminopyridine, pipera- Zine, piperidine;(4) aralkylamines such as cz-methylbenzylamine, phenethylamine; (5)cycloalkylamines such as cyclohexylamine; (6) alkaloids such as quine,cinchonidine, cinchonine, ephedrine.

Representative compounds of this invention which are particularly usefulare as follows:

oz-methyLm-mercapto-Ii-chloro-4-cyclohexylphenylacetic acidoz-methyl-z-acetylthio-3chloro4-cyclohexylphenylacetic acida-methyl-ar-propionylthio-3chloro-4-cyclohexylphenylacetic acidor-methyl-oi-butyrylthio-3-chloro-4-cyclohexylphenylacetic acida-methyl-oz-butenoylthio-3-chloro-4-cyclohexylphenylacetic acidoz-methyl-a-benzoylthio-3-chloro-4-cyclohexylphenylacetic acidcx-methyl-a-(0'-toluoylthio)-3-chloro-4-cyclohexylphenylacetic acida-methyl-oz-(0'-carboxybenzoylthio)-3-chloro4- cyclohexylphenylaceticacid a-methyl-0z-methoxythiocarbonylthio-3-chloro-4-cyclohexylphenylacetic acidoz-methyl-az-ethoxythiocarbonylthio-3-chloro-4- cyclohexylphenylaceticacid 6 a-methyl-oz-methoxycarbonylthio-3-chloro-4-cyclohexylphenylacetic acid a-rnethyl-oz-ethoxycarbonylthio-3-chloro-4-cyclohexylphenylacetic acidoz-methyl-oz-benzyloxycarbonylthio-3-ch1oro-4- cyclohexylphenylaceticacid a-methyl-oz-thioformylthio-3-chloro-4-cyclohexylphenylacetic acidot-methyl-a-amidinothio-3-chloro-4-cyclohexylphenylacetic acidoz-methyl-oz-thiocyanato-3-chloro-4-cyclohexylphenylacetic acid0z-methyl-0z-thiosulfo-3-chloro-4-cyclohexylphenylacetic acidoz-rnethyl-wcarbamylthio-3-chloro-4-cyclohexylphenylacetic acidoz-methyl-oz-ethylcarbamylthio-3-chloro-4-cyclohexylphenylacetic acidcz-methyl-oz-dimethylcarbamylthio-3-chloro-4- cyclohexylphenylaceticacid a-methyl-oz diethylcarbamylthio-3-chloro-4 cyclohexylphenylaceticacid or-methyl-oz-methylthio3chloro-4-cyclohexylphenylacetic acidoz-methyLoz-ethylthio-3-chloro-4-cyclohexylphenylacetic acida-methyl-oz-propylthio-3-chloro-4-cyclohexylphenylacetic acidoz-methyl-oz-i-propylthio-3-chloro4-cyclohexylphenylacetic acidoz-methyl-oz-methylsulfinyl-3chloro-4-cyclohexylphm ylacetic acida-rnethyl-oz-methylsulfonyl3-chloro-4-cyclohexylphenylacetic acidaz-methyl-a-sulfino-3-chloro-4-cyclohexylphenylacetic acidoz-methyl-wsulfo-3-chloro-4-cyclohexylphenylacetic acida-methyl-a-acetylthio-3-fluoro-4-cyclohexylphenylacetic acida-methyl-oz-acetylthio-3-bromo-4-cyclohexylphenylacetic acidamethyl-a-acetylthio-3-iodo4- cyclohexylphenylacetic acidoz-methyl-oz-acetylthio-3-nitro-4-cyclohexylphenylacetic acidoz-methyl-oz-acetylthio-B-trifluoromethyl-4-cyclohexylphenylacetic acidzx-methyl-a-acetylthio-3-mercapto-4-cyclohexylphenylacetic acidoz-methyl-ot-acetylthio-3-acetylthio-4-cyclohexylphenylacetic acidoz-methyl-a-acetylthio-3-methylmercapto-4- cyclohexylphenylacetic acidoz-methyl-oz-acetylthio-3-methylsulfinyl-4-cyclohex ylphenylacetic acidoz-methyl-oz-acetylthio-3-methylsulfonyl-4-cyclohexylphenylacetic acida-methyl-cr-acetylthio-3-cyano-4cyclohexylphenylacetic acidoz-methylacetylthio-3-carboxy-4-cyclohexylphenylacetic acidoz-methyl-0z-acetylthio-3-carbethoxy-4-cyclohexylphenylacetic acida-methyl-a-acetylthio3-amino4-cyclohexylphenylacetic acidoz-methyl-oz-acetylthio-3acetylamino-4cyclohexylphenylacetic acid doz-n'iethyl-a-acetylthio-3-chloro-4-cyclohexylphenylacetic acid,piperazinium salt 1oz-methyl-oz-acetylthio-S'-chloro-4-cyclohexylphenylacetic acid,piperazinium salt da-methyl-oi-acetylthio-34:hloro-4-cyclopentylphenylacetic acid 1oz-methyl-a-acetylthio-3-chloro-4-cyclopentylphenylacetic acid doz-methyl-a-acetylthio-S,5-dichloro-4-cyclopentylphenylacetic acid 1oz-methyl-oz-acetylthio-3,5-dichloro-4-cyclopentylphenylacetic acid dot-methyl-uz-mercapto-3-chloro-4-cyclopentylphenylacetic acid 1a-methyl- -mercapto-3-chloro-4-cyclopentylphenylacetic acid doz-methyl-abenzoylthio-3,5-dichloro-4-cyclopen tylphenylacetic acid Ioz-methyl-a-benzoylthio-Ii,5dichloro-4-cyclopentylphenylacetic acid daz-methyl-a-diethylcarbamylthio-3-chloro-4- cyclopentylphenylacetic acid1 a-methyl-oz-diethylcarbamylthio-3-chloro-4- doz-methyl-ctmercapto-3-chloro-4-cycloheptylphenylacetic acid 1amethyLa-mercapto-3-chloro-4-cycloheptylphenylacetic acid doz-methyl-a-benzoylthio-B,5-dichloro-4-cyclohep tylphenylacetic acid Ia-mcthyl-oz-benzoylthiod,5-dichloro-4--cycloheptylphenylacetic acid da-methyl-oz-diethylcarbamylthio-3-chloro-4- cycloheptylphenylacetic acid1 oz-methyl-cz-diethylcarbamylthio-3-chloro-4- cycloheptylphenylaceticacid d oz-methyl-oz-ethoxythiocarbonylthio-3,S-dichloro-4-cycloheptylphenylacetic acid Ioz-methyl-i-ethoxythiocarbonylthio-3,5-dichloro-4-cycloheptylphenylacetic acid da-methyl-oz-acetylthio-3-chloro-4-cycloheptylphenylacetic acid, sodiumsalt 1 ct-methyLaz-acetylthio-3-chloro-4-cycloheptyl phenylacetic acid,sodium salt az-ethyl-oz-mercapto-3-chloro-4-cyclohexylphenylacetic acidoz-ethyl-oz-acetylthio-3-chloro-4-cyclohexylphenylacetic acidoz-ethyl-a-methoxycarbonylthio-3-chloro-4- cyclohexylphenylacetic acid Moz-ethyl-oz-thioformylthio-3-chloro4-cyclohexylphenylacetic acidoz-ethyl-a-rnethoxythiocarbonylthio-3-chloro-4- cyclohexylphenylaceticacid oz-ethyl-a-ethylcarbamylthio-3-chloro-4-cyclohexylphenylacetic acidoz-ethyl-oz-sulfino-3-chloro-4-cyclohexylphenylacetic acidoz-ethyl-oz-sulfo-3-chloro-4-cyclohexylphenylacetic acidoz-ethyl-oz-acetylthio-3-fluoro-4-cyclohexylphenylacetic acidoz-ethyl-a-acetylthio-3-bromo-4-cyclohexylphenylacetic acidoz-ethyl-oz-acetylthio-3-nitro-4-cyclohexylphenylacetic acidoz-ethyl-oO-acetylthio-3-trifluoromethyl-4-cylclohexylphenylacetic acidoz-ethyl-oz-acetylthio-3-methylsulfonyl-4-cyclohexylphenylacetic acidoz-ethyl-oz-acetylthio-3,5-dichloro-4-cyclohexylphenylacetic acida-ethyl-ot-acetylthio-3-chloro5-fluoro-4-cyclohexylphenylacetic acidoz-ethyl-oz-acetylthio-3-chloro-5-bromo-4-cyclohexylphenylacetic acida-ethyl-a-acetylthio-3-chloro-5-nitro-4-cyclohexylphenylacetic acidoz-ethyl-a-acetylthio-3-chloro-5-methylsulfonyl4- cyclohexylphenylaceticacid a-ethyl-a-acetylthio-3-chloro-5-tritluoromethyl-4-cyclohexylphenylacetic acid oz-ethyl-oz-acetylthio-3,5-dibromocyclohexylphenylacetic acidoz-propyla-acetylthio-3-chloro-4-cyclohexylphenylacetic acid methyla-ethyl-a-acetylthio-3-chloro4-cyclohexylphenylacetic acid ethyl methyla-acetylthio-3-chloro-4-cyclohexylphenylacetic acid N,l l-diethyla-ethyl- -acetylthio-3-chloro-4- cyclohexylphenylacetic acidoz-ethyLa-acetylthio-3-chloro-4-cyclohexylphenylacetic acid, sodium saltoz-ethyl-oz-acetylthio-3-chloro-4-cyclohexylphenylacetic acid,diethylammonium salt a-ethyl-oz-acetylthio-3-chloro-4-cyclopentylphenylacetic acidoz-ethyl-a-acetylthio-3-chloro-4-cycloheptylphenylacetic acid cloz-ethyl-0z-acetylthio-3-chloro-4-cyclohexylphenylacetic acid 1oz-ethyl-a-acetylthio-3-chloro-4-cyclohexylphenylacetic acid Thecompounds of this invention may be prepared by the following generalprocedures. Condensation of a cycloalliylbenzene with a loweralkyl oraralkyl oxalyl chloride in the presence of anhydrous aluminum chlorideresults in a p-cycloalkylphenylglyoxylate. The resulting loweralkyl oraralkyl esters of the p-cycloalkylphenylglyoxylic acid may then be (a)halogenated; (b) nitrated or (c) alkylated to obtain the correspondingloweralkyl esters of a 3-halo-4-cycloalkylphenylglyoxylic acid, a3-nitro4-cycloalkylphenylglyoxylic acid or a 3-allyl-4-cycloalkylphenylglyoxylic acid. Chlorination or bromination may becarried out in the presence of a small amount of iodine dissolved in aninert solvent 15 16 such as carbon tetrachloride. A solution of'chlorineor bromine is then added while the temperature is held near 0C.Nitration is carried out with fuming nitric acid at about 0C. Alkylationis carried out under Friedel Crafts conditions with an alkyl halide andalumi- 5 num chloride. The following reaction equations illustrate thesemethods.

l g IIVHI) (I. I

Al k v where R" is loweralkyl or arloweralkyl and Hal is 35 chloro orbromo.

When a loweralkyl group is desired in the cycloalkyl ring, then thecondensation will take place with the appropriate loweralkyl benzenecycloalkyl followed by nitration, chlorination, bromination oralkylation as de- 40 sired.

o 0 u r zln Cl-C-COOR" (CH c-coon Al Cl 3 Alk-C] C1 or Br A161 2 2 l8Appropriately desired end products having various R c. reacted withcuprous methanesulfinate in quinoand R substituents can be prepared byusing suitable line at about 150C to obtain a 3-methylsulfonyl-4-reactions in order to convert one group to another.

cycloalkylphenylglyoxylate:

0 (CH u 2 -cooR" 0150 01,, (CH C-COOR Thus, for example, a3-halo-4-cycloalkylphenylglyoxy- A 3-nitro-4-cycloalkylphenylglyoxylatemay be seleclate in which halo is chloro, bromo or iodo may be tivelyhydrogenated to the corresponding amine.

8 B 0 a a R" H -c00R" 2 n C C00 2 (CH 0 a. reacted with cuprous cyanidein quinoline at about A 3-amino-4-cycloalkylphenylglyoxylate may then150C to produce a 3-cyano-4-cycloalkylphenylglyoxybe late: a. monoordialkylated with loweralkyl halides or 0 (cn l l ll u C @C'COORH Hal CNb. reacted with trifluoromethyliodide and copper sulfates or acylatedwith loweracyl chlorides or anhypowder at about 150C indimethylformamide to obtain 5 drides,

o 0 H II 00R" R"X C-COOR (cH C C NH NHR" R"COCl or RHX (R"CO) O C-COOR"(04 c coo (cu NHCOR" um") a 3mmuoromethy1 4 CycloalkylphenylglyoxylateIb. diazotized to the dlazonlum fluoroborate whlch is described inTetrahedron Letters: 47, 4095 (1959)] then thermally decomposed to the3-fluoro-4-cycloalk- 6O ylphenylglyoxylate,

C-COOR" Cu Hal s v i n -CO0R 2 (94 C-COOR HBF N BF

c.' diazotize d and heated in an aqueous medium to d. diazotizedfollowed by a Sandmeyer type reaction form the'3-hydroxy-4-cycloalkylphenylglyoxylate or to yield the halo group,heated in an alcoholto form the 3-alkoxy-4-cycloalkylphenylglyoxylate.The hydroxyl group may also be 211- 45 e. diazotized and heated with anaqueous solution of kylated with loweralkyl halides or sulfates to thealkb s i i did to prepare h 3-i d -4 1k oxyl group or acylated withloweracyl chlorides oran- 5 phenylglyoxylate,

hydrides to the acyloxy compound in the presence of a tertiary aminesuch as pyridine,

won)

HNO. z n c cooR 2 f. diazotized followed by reaction with potassiumethylxanthate followed by hydrolysis to obtain 3-mercapto-4-cycloalkylphenylglyoxylic acid which can be esterified to a3-mercapto-4-cycloalkylphenyl- 10 glyoxylate. This in turn can be loweralkylated to the lower alkylthio and oxidized to the loweralkylsulfinyland loweralkylsulfonyl groups or acylated to the acylthio compounds.

A second nitration or halogenation with chlorine or ing3,5-disubstituted-4-cycloalkylphenylglyoxylate. This may be carried outat any appropriate stage of the synthesis in order to obtain the desiredsubstituents. Thus, for example, a 3-chloro-4-cycl0alkylphenylglyoxylatemay be nitrated as above to obtain a 3-chloro-S-nitro-4-cycloalkylphenylglyoxylate or chlorinated to obtain a3,5-dichloro-4-cycloalkylphenylglyoxylate. A3-nitro-4-cycloalkylphenylglyoxylate can 0 ll C-COOR" S OR" be nitratedto give a 3,5-dinitro-4-cycloalkylphenylbromine may be carried out onthe 3-substituted-4- 5O glyoxylate. A 3-alkyl compound may also benitrated,

cycloalkylphenylglyoxylate to obtain the correspondchlorinated orbrominated to the 3-chloro 3-bromo or 3-nitro-5-alkyl compounds.

Cl (Br) 0 0 II I Cl or Br g COOR c-cooR 0 II M HNO3 n c400 KH C-COOR"Alk In turn, a 3'-chlor0-5-nitro-4-cycloalkylphenylglyoxylate can bereduced to a corresponding 3-chloro-5-amin0-4-cycloalkylphenylglyoxylate. This may then be monoor di-alkylatedor acylated. The amine may also be converted via the diazonium salt to avariety of derivatives as described above.

As a further example of disubstitution, a 3-chlor0-5-nitro-4-cycloalkylphenylglyoxylate can be reacted with cuprous cyanidein quinoline at 150C to obtain a 3-cyano-S-nitro-4-cycloalkylphenylglyoxylate; or with Cl (N02) is NHCOR"(cH l 5 cycloalkylphenylglyoxylate;

Alk

trifluoromethyl iodide and copper powder in quinoline at 150C to obtaina 3-trifluoromethyl-5-nitr0-4- or with cuprous methanesulfinate inquinoline at 150C to a 3-methylsulfonyl-S-nitro-4-cycloalkylphenylglyoxylate. Still anotherexample of various disubstitution would be the selective reduction of a3,5-dinitro-4-cycloalkylphenylglyoirylate with hydrogen or ammoniumsulfide to obtain a 3-nitro-5-amino-4-cycloalkylphenylglyoxylate whichin turn can be diazotized to the various derivatives.

5 N02 i ii II C-COOR" CuCN H c coon CuSO CH fi KH C-COOR" NH 0 s 2 0 2II c-coon" (CH c-cooa" r (NH S a 'NHR" o fi (01 c-coor' CI(NO2) RIIXII Ou (CH C-COOR' HNo [I m.)- iu y C-COOR cuwo a CH HNo O H o b H I 2 (01c-coon' CHNO2) B RII fi HNO R"OH z n c-co'ok" C1(NO2) B NH B Br (CH c R"n 2 n c- 00 HMO (CH CCO0R CuBr c1 (N02) c1(No HNO Cul (04 C-COOR OICHNOZ) B cm [1 R" lkl o w are IS ower u y HNO2 (01 c-cooc" 8 SH ilHNOKSCS0C2H5 CH 2) NuOH c g? Cl(NO l Of course, other reactions may becarried out on the 50 trated, chlorinated or brominated as above andagain,

above products by diazotization to obtain the desired in turn, convertedto the various desired substituents. substituents as previouslydescribed. Thus, for example, a 3-fluoro-4-cycloalkylphenyl- Variousmono-substituted products may also be niglyoxylate may be nitrated orbrominated and the nitro and bromo groups converted to varioussubstituents.

II II (CH l c-cooR" 2 HNO3 (CH c COOR CuCN Thep-cycloalkylphenylglyoxylate may then be re r to thea-alkyl-3-nitro-4-cycloalkylphenylglycolate or acted with one equivalentof a Grignard reagent-1ooz-alkyl-3-ch]oro-5-nitro-4-cycloalkylphenylglycolate. form thea-substituted p-cycloalkylphenylglycolate.- This in turn may then becatalyticall y reduced to the This may then be hydrolized to acid. a-alkyl-3-amino-4-cycloalkylphenylglycolate or a-al- It is often moreconvenient to convertone subs t ituen tj 45 l/ ""l/"= y p l ll toanother after the Grignard reaction to the glycolat'e, The m 8 y bediazotizefi as above to Thus, for example, a3-nitro-4-cycloalkylphenylgly y, the desired substituents. This may becarried out on any late or a 3-chloro-5nitro-4-cycloalkylphenylglyoxylate of the nitro compounds as outlined.The diazotized may be reacted with an alkyl Grignard reagentas above 50products may then be hydrolyzed to the glycolic acid.

c-cooR" 2 diuzoti lotion where R" is lower alkyl H NOH (CH n Theglycolate esters may be hydrolyzed to the correspondingp-cycloalkylphenylglycolic acid. Reaction of the glycolate ester orglycolic acid with an acid chloride YCl or acid anhydride YOY in thepresence of a tertiary amine such as pyridine, picoline, or quinolineresults in the formation of an hydroxy derivative of the c-coNHR" A C-COH A OH I glycolate' Examples of YCl and YOY incldde acetyla-halo-4-cycloalkylphenylacetate is prepared.

ococu cu coon c com-HR") B R, on

(cu c coomn" R R OCOCH= CHCOOH c-cooma) O= 1:0

ococ rucoou where C-COH(R") R" is lower alkyl I Hul l i -cooa" Re The3-cyanoglycolate may also be reacted with two 35 Where Z iS as describedin C01. 2. equivalents of methylmagnesium iodide in tetrahydro Where Halis qh r iOdO- furan followed by hydrolysis t b i h 3 Reactionqfariq-sulfonate with ametal halide (preferably an alkali halide)results in the corresponding acetylglycolic acid. .1 r.

a-halo compound.

zlaso Ruu) 3 B V where Z is as described'onpage 4.7,

l The corresponding a-haloacetic acid may be pre- CH g pared by heatingthe ester with acetic acid containing 2 n l the corresponding hydrogenhalide.

RC 'r;-- CN 1) MeMgI 5 2) H 0 H J 3-1 n I COO a C0CH When a substituted4-tcycloalkylpheiiylglycolate' 'is reacted with a phosphorus trihalide,phosphorus pentahalide, phosphorus oxyhalide, sulfurylhalide; thionylhalide, or sulfur halide, the corresponding substituted where R is loweralkyl. where:

The acid addition salts may then be formed by the ac- Z is NH tion ofone equivalent of a suitable base with the substiloweralkylamine, tuteda-halo-4-cycloalkylphenylacetic acid. Suitable diloweralkylamino, basesthus include for example the alkali metal alkox- 5 cycloloweralkylamino,ides such as sodium methoxide, etc., and the alkali A metal and alkalineearth metal hydroxides, carbonates, N\l/A (where A is loweralkylidenylor heterolowe bicarbonates, etc. (such as sodium hydroxide,potasralkylidenyl), sium hydroxide, calcium hydroxide, potassiumcarbonate, sodium bicarbonate, magnesium bicarbonate, NHOI-l or etc.).Also, the aluminum salts of the instant products Nl-lNl-l may beobtained by treating the corresponding sodium salt with an appropriatealuminum complex such as aluminum hydroxy chloride hexahydrate, etc. Theammonium salts may be made by reaction with the corresponding amine suchas methylamine, diethylamine, B-hydroxyethylamine, piperazine,piperidine, a-me- B thylbenzylamine, cycloahexylamine, triethylamine,NH3 T phenethylamine, etc. (cu 2)n |CCONH2 B R' n l'ilal R (04 ?-COOH BHal P NH2R" I a R (01 l -coumz" Hal l (awn c-coou R l s R IR Hal HN(R")2Reaction of a substituted ahalo-p-cycloalkylpheny- 04 c--cor-i(R")lacetate ester with a nitrogen base such as ammonia, loweralkylamine,diloweralkylamine, cycloloweralkyla- R Ra a a R Hal A Hal H (m l cH (04(II-COOK!" L (01 cc N l R 0 :1 a

where R is loweralkyl. B mine, a nitrogen containing hetero compoundsuch as m r A piperidine, morpholine, piperazine results in the corre-(01 c-coN A sponding amide. The acetate ester with hydroxylamine L givesthe corresponding hydroxamic acid, and with by n drazine gives thecorresponding hydrazide.

o B R B R Hal llal & (CH f- 9 2 n 0 iflcoz Ra R Ru R lllal (CH2)n-(I-COZ

1. A COMPOUND OF THE FORMULA
 2. A compound according to claim 1 which isdextrorotatory.
 3. A compound according to claim 1 which islevorotatory.
 4. A compound according to claim 1 of the formula
 5. Acompound according to claim 4 where: R is halo or haloloweralkyl; R'' ishydrogen, chloro or bromo; X is amidinothio; and Z is -OH, loweralkoxy,benzyloxy or -OM.
 6. Alpha -methyl- Alpha-amidinothio-3-chloro-4-cyclohexylphenylacetic acid.